Tarik F. Massoud, MD, PhD

Professor of Radiology (General Radiology) at the Stanford University Medical Center

Bio

Bio

Tarik Massoud is a Professor of Neuroradiology and Molecular Imaging in the Department of Radiology, Stanford University School of Medicine, where he directs LEMNI (the Laboratory of Experimental and Molecular Neuroimaging), and is an Attending Neuroradiologist in Stanford Health Care. He qualified from the Medical School of the Royal College of Surgeons in Ireland and then served as intern to two inspirational medical giants of their days, Dr. William H. (Willie) Bisset at the Royal Hospital for Sick Children in Edinburgh, UK, and Professor Sir Raymond (Bill) Hoffenberg, PRCP, at the Queen Elizabeth Hospital in Birmingham, UK. He trained in Radiology and Neuroradiology in Oxford, UCLA, and the University of Michigan, and is a Fellow of the Royal College of Radiologists in London. He holds a research MD degree (NUI) in experimental neuroimaging (work conducted at UCLA), and a Cambridge PhD in molecular imaging (work conducted at the Crump Institute for Molecular Imaging at UCLA, and the Molecular Imaging Program at Stanford, Gambhir laboratory). From 2000 to 2013 he was a University Lecturer and Honorary Consultant in Neuroradiology at the University of Cambridge School of Clinical Medicine and Addenbrooke?s Hospital in Cambridge, UK. He was formerly an Assistant and Associate Professor of Radiology at UCLA, and held visiting Associate Professorships at Columbia and MCW, Milwaukee. He has published extensively and won numerous awards at scientific meetings. His papers in experimental interventional neuroradiology and molecular imaging are widely cited. He has been a peer reviewer for 35 international medical journals, as well as other medical charities and governmental funding agencies. He is Editor-in-Chief of the journal Reports in Medical Imaging, and an editorial board member for numerous biomedical journals. In 2016 he was awarded a Special Faculty Permit (eminent physician license) by the Medical Board of the State of California.

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Research & Scholarship

Current Research and Scholarly Interests

My current interests are in molecular and translational imaging of the brain especially in neuro-oncology and cerebrovascular diseases, experimental aspects of neuroimaging, clinical neuroradiology, neuroradiological anatomy, and research education and academic training of radiologists.

Clinical Trials

This clinical trial compares fluorine F 18 fluorodopa (18F FDOPA) positron emission
tomography (PET) with standard magnetic resonance imaging (MRI) in measuring tumors in
patients with glioma that is newly diagnosed or recurrent (has returned). 18F FDOPA is a
radioactive drug that binds to tumor cells and is captured in images by PET. Computed
tomography (CT) and MRI are used with PET to describe information regarding the function,
location, and size of the tumor. PET/CT or PET/MRI may be more accurate than standard MRI in
helping doctors find and measure brain tumors.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrei Iagaru, 650-736-2859.

Abstract

Aberrant protein folding represents the molecular basis of many important human diseases. Although the discovery of new anti-misfolding drugs is a major priority in molecular therapeutics, there is currently no generalizable protein folding assay for use in cell-based high throughput screening (HTS) of chemical libraries, or for in vivo imaging. We molecularly engineered a bioluminescence-based biosensor composed of rationally split Firefly luciferase reporter fragments flanking a test protein, and used this in a protein-fragment complementation assay to quantitatively measure folding of the test protein. We comprehensively validated this biosensor in vitro, in cells, and by optically imaging protein folding and misfolding in living mice using several test proteins including enhanced green fluorescent protein, Renilla luciferase, Gaussia luciferase, and SIRT1. Applications of this novel biosensor are potentially far-reaching in both cell-based HTS approaches to discover new anti-misfolding drugs, and when using the same biosensor in validation studies of drug candidates in small animal models.Novel anti-misfolding drugs are needed as molecular therapeutics for many diseases. We developed first in vivo imaging protein folding biosensor to aid drug discovery. Biosensor created by flanking a test protein with rationally split Firefly luciferase. Biosensor validated by detecting folding of test proteins EGFP, Rluc, Gluc, and SIRT1. Generalizable molecular biosensor for translational applications in drug screening.

Abstract

BACKGROUND:: Transvenous retrograde nidus sclerotherapy under controlled hypotension (TRENSH) is a proposed novel concept for endovascular treatment of cerebral arteriovenous malformations (AVMs). OBJECTIVE:: To assess the experimental hemodynamic feasibility of TRENSH in a pig AVM model. METHODS:: We surgically constructed carotid-jugular fistula-type AVM models in eight pigs. In five pigs (Group 1) we hemodynamically assessed the AVM through the main arterial feeder (AF) and draining vein (DV) at systemic normotension (Systnorm). We then performed retrograde nidus angiography through the DV at progressively deeper levels of hemorrhagic systemic hypotension (Systhypo), and graded and correlated these angiograms with the degree of Systhypo. In another three pigs (Group 2) we correlated the effects of temporary balloon occlusion of the main AF with the angiographic extent of retrograde nidus filling. RESULTS:: In Group 1 pigs, the drop in AF pressure correlated strongly (r=0.93-0.99) with the drop in DV pressure at progressively deeper Systhypo. Minimal retrograde nidus filling occurred at Systnorm. We observed progressively greater extents of retrograde nidus filling as the transnidal pressure gradients fell with deeper Systhypo. Near-complete retrograde permeation of the nidus was possible as the transnidal gradients approached zero mmHg. As more of the nidus filled, its concurrent emptying was documented through a greater number of DVs. Temporary AF occlusion resulted in improved retrograde nidus filling in all Group 2 pigs. CONCLUSION:: Endovascular TRENSH appears feasible in a pig AVM model. Further experimental investigations of TRENSH are necessary to assess its full potential prior to future clinical applications.

Abstract

In this second article, we review the various strategies and applications that make use of reporter genes for molecular imaging of the brain in living subjects. These approaches are emerging as valuable tools for monitoring gene expression in diverse applications in laboratory animals, including the study of gene-targeted and trafficking cells, gene therapies, transgenic animals, and more complex molecular interactions within the central nervous system. Further development of more sensitive and selective reporters, combined with improvements in detection technology, will consolidate the position of in vivo reporter gene imaging as a versatile technique for greater understanding of intracellular biologic processes and underlying molecular neuropathology and will potentially establish a future role in the clinical management of patients with neurologic diseases.

Abstract

In this first article, we review the basic principles of using reporter genes for molecular imaging of the brain in living subjects. This approach is emerging as a valuable tool for monitoring gene expression in diverse applications in laboratory animals, including the study of gene-targeted and trafficking cells, gene therapies, transgenic animals, and more complex molecular interactions within the central nervous system. Further development of more sensitive and selective reporters, combined with improvements in detection technology, will consolidate the position of in vivo reporter gene imaging as a versatile method for greater understanding of intracellular biologic processes and underlying molecular neuropathology and will potentially establish a future role in the clinical management of patients with neurologic diseases.

Abstract

Molecular imaging is a rapidly emerging field, providing noninvasive visual quantitative representations of fundamental biological processes in intact living subjects. Fundamental biomedical research stands to benefit considerably from advances in molecular imaging, with improved molecular target selection, probe development and imaging instrumentation. The noninvasiveness of molecular imaging technologies will also provide benefit through improved patient care. Molecular imaging endpoints can be quantified, and therefore are particularly useful for translational research. Integration of the two disciplines of molecular imaging and molecular medicine, combined with systems-biology approaches to understanding disease complexity, promises to provide predictive, preventative and personalized medicine that will transform healthcare.

Abstract

In the past few years there has been a veritable explosion in the field of reporter gene imaging, with the aim of determining the location, duration and extent of gene expression within living subjects. An important application of this approach is the molecular imaging of interacting protein partners, which could pave the way to functional proteomics in living animals and might provide a tool for the whole-body evaluation of new pharmaceuticals targeted to modulate protein-protein interactions. Three general methods are currently available for imaging protein-protein interactions in living subjects using reporter genes: a modified mammalian two-hybrid system, a bioluminescence resonance energy transfer (BRET) system, and split reporter protein complementation and reconstitution strategies. In the future, these innovative approaches are likely to enhance our appreciation of entire biological pathway systems and their pharmacological regulation.

Abstract

Homodimeric protein interactions are potent regulators of cellular functions, but are particularly challenging to study in vivo. We used a split synthetic renilla luciferase (hRLUC) complementation-based bioluminescence assay to study homodimerization of herpes simplex virus type 1 thymidine kinase (TK) in mammalian cells and in living mice. We quantified and imaged homodimerization of TK chimeras containing N-terminal (N-hRLUC) or C-terminal (C-hRLUC) fragments of hRLUC in the upstream and downstream positions, respectively (tail-to-head homodimer). This was monitored using luminometry (68-fold increase, and was significantly [P<0.01] above background light emission) and by CCD camera imaging of living mice implanted with ex vivo transfected 293T cells (2.7-fold increase, and is significantly [P<0.01] above background light emission). We also made a mutant-TK to generate N-hRLUC mutant TK and mutant TK-C-hRLUC by changing a single amino acid at position 318 from arginine to cysteine, a key site that has previously been reported to be essential for TK homo-dimerization, to support the specificity of the hRLUC complementation signal from TK homodimerization. Ex vivo substrate (8-3H Penciclovir) accumulation assays in 293T cells expressing the TK protein chimeras showed active TK enzyme. We also devised an experimental strategy by constructing variant TK chimeras (possessing extra N-hRLUC or C-hRLUC 'spacers') to monitor incremental lack of association of the tail-to-head TK homodimer. Application of this potentially generalizable assay to screen for molecules that promote or disrupt ubiquitous homodimeric protein-protein interactions could serve not only as an invaluable tool to understand biological networks but could also be applied to drug discovery and validation in living subjects.

Abstract

A laboratory-based study of the physical and performance characteristics of a new 0.25-mm-thin microangioscope was performed. The microangioscope tested was compatible with currently available microcatheters, but its tip was considerably stiff and of limited radiopacity. Poor image quality and difficult image interpretation were further drawbacks. Intensive efforts are directed at addressing current limitations and testing further innovations that could pave the way for future performance in neurovascular endoscopy.

Abstract

A novel biomathematical arteriovenous malformation (AVM) model based on electric network analysis was used to investigate theoretically the potential role of intranidal hemodynamic perturbations in elevating the risk of rupture after simulated brain AVM radiosurgery.The effects of radiation on 28 interconnected plexiform and fistulous AVM nidus vessels were simulated by predefined random or stepwise occlusion. Electric circuit analysis revealed the changes in intranidal flow, pressure, and risk of rupture at intervals of 3 months during a 3-year latency period after simulated partial/complete irradiation of the nidus using doses <25 and >/=25 Gy. An expression for risk of rupture was derived on the basis of the functional distribution of the critical radii of component vessels. The theoretical effects of radiation were also tested on AVM nidus vessels with progressively increasing elastic modulus (E:) and wall thickness during the latency period, simulating their eventual fibrosis.In an AVM with E=5. 0x10(4) dyne/cm(2), 4 (14.3%) of a total 28 sets of AVM radiosurgery simulations revealed theoretical nidus rupture (risk of rupture >/=100%). Three of these were associated with partial nidus coverage and 1 with complete treatment. All ruptures occurred after random occlusion of nidus vessels in AVMs receiving low-dose radiosurgery. Intranidal hemodynamic perturbations were observed in all cases of AVM rupture; the occlusion of a fistulous component resulted in intranidal rerouting of flow and escalation of the intravascular pressure in adjacent plexiform components. Risk of rupture was found to correlate with nidus vessel wall strength: a low E: of 1.9x10(4) dyne/cm(2) resulted in a 92.8% incidence of AVM rupture, whereas a higher E: of 7.0x10(4) dyne/cm(2) resulted in only a 3.6% incidence of AVM rupture. A dramatic reduction in rupture incidence was observed when increasing fibrosis of the nidus was modeled during the latency period.It was found that the theoretical occurrence of AVM hemorrhage after radiosurgery was low, particularly when radiation-induced fibrosis of nidus vessels was considered. When rupture does occur, it would appear from a theoretical standpoint that the occlusion of intranidal fistulas or larger-caliber plexiform vessels could be a significant culprit in the generation of critical intranidal hemodynamic surges resulting in nidus rupture. The described AVM model should serve as a useful research tool for further theoretical investigations of cerebral AVM radiosurgery and its hemodynamic sequelae.

Abstract

The experimental induction of histologic transformations in microvessels of similar caliber to those of nidus vessels of cerebral arteriovenous malformations (AVMs) has not been attempted previously. Our goal was to examine preliminarily the histopathologic characteristics of nidus vessels and the angiographic features of a chronic AVM model in swine.AVM models were fashioned from bilateral carotid retia mirabilia of seven swine after the surgical formation of large unilateral carotid-jugular fistulas. One AVM model was made for immediate use, whereas in the other six, follow-up angiography was obtained at varying intervals (2 to 180 days) after model creation. Light and electron microscopy, immunohistochemistry (using monoclonal antibodies against smooth muscle actin and PC10 against proliferating cell nuclear antigen), and histometry were performed on the nidus vessels of three swine: one acutely created, one 2 months old, and one 6 months old.Vascular dilatation and tortuosity of the main arterial feeder and draining vein were evident angiographically as early as 4 days after AVM creation, and were maximal in the 6-month-old model. Compared with the acutely created nidus vessels, those in the two chronic models revealed disrupted and attenuated elastica and intimal hyperplasia that was focal ("cushions") or generalized, leading to luminal occlusion. Variable numbers of cells in the tunica media of chronic nidus vessels contained smooth muscle actin. PC10/proliferating cell nuclear antigen immunoreactivity was observed in the endothelium and subendothelial layers. Histometry showed increases in intimal hyperplasia and medial thickness in the chronic vessels.Nidus vessels in this chronic swine AVM model exhibited striking histologic changes similar to those seen in cerebral AVMs. The induced vessel growth seen angiographically and histologically in components of the chronic AVMs was consistent with the presence of persistently raised intravascular hemodynamic loads. This preliminary feasibility study suggests that the realistic histologic characteristics of this chronic AVM model are an attractive feature, and if confirmed in future, more comprehensive, studies would be of benefit in accurate histopathologic interpretation of the effects of superimposed experimental embolotherapy or radiosurgery. This model may provide a useful experimental tool to study the dynamic cellular and tissue events that dictate the development and natural history of AVMs.

Abstract

Nidus rupture is a serious complication of intracranial arteriovenous malformation (AVM) embolotherapy, but its pathogenetic mechanisms are not well described. An AVM model based on electrical network analysis was used to investigate theoretically the potential role of hemodynamic perturbations for elevating the risk of nidus vessel rupture (Rrupt) after simulated AVM embolotherapy, and to assess the potential benefit of systemic hypotension for preventing rupture.Five separate hypothetical mechanisms for nidus hemorrhage were studied: 1) intranidal rerouting of blood pressure; 2) extranidal rerouting of blood pressure; 3) occlusion of draining veins with glue; 4) delayed thrombosis of draining veins; and 5) excessively high injection pressures proximal to the nidus. Simulated occlusion of vessels or elevated injection pressures were implemented into the AVM model, and electrical circuit analysis revealed the consequent changes in intranidal flow, pressure, and Rrupt for the nidus vessels. An expression for Rrupt was derived based on the functional distribution of the critical radii of component vessels. If AVM rupture was observed (Rrupt > or = 100%) at systemic normotension (mean pressure [P] = 74 mm Hg), the theoretical embolization was repeated under systemic hypotension (minor P = 70 mm Hg, moderate P = 50 mm Hg, or profound P = 25 mm Hg) to assess the potential benefit of this maneuver in reducing hemorrhage rates.All five pathogenetic mechanisms under investigation were able to produce rupture of AVMs during or after embolotherapy. These different mechanisms had in common the capability of generating surges in intranidal hemodynamic parameters resulting in nidus vessel rupture. The theoretical induction of systemic hypotension during and after treatment was shown to be of significant benefit in attenuating these surges and reducing Rrupt to safer levels below 100%.The induction of systemic hypotension during and after AVM embolization would appear theoretically to be of potential use in preventing iatrogenic nidus hemorrhage. The described AVM model should serve as a useful research tool for further theoretical investigations of AVM embolotherapy and its hemodynamic sequelae.

Abstract

An alternative endovascular treatment to conventional transarterial embolization of cerebral arteriovenous malformations (AVMs) is proposed.According to this proposed treatment, selected AVMs could undergo transvenous retrograde nidus sclerotherapy under controlled hypotensive anesthesia (TRENSH).It is hypothesized that TRENSH may provide the means of avoiding delivery of embolic agents via arterial feeders (thus preventing ischemic complications), in addition to a possible more complete permeation of an AVM nidus with a sclerosant than can otherwise be obtained with current agents via arterial feeders.Instead of relying on access to an AVM nidus from the arterial side (with its usual complexity), TRENSH would require retrograde access to the lesion via much larger and anatomically simpler draining veins. Retrograde permeation of the AVM nidus may then be possible with a liquid sclerosant (to effect a "chemical embolization") provided that the arterial inflow is reduced sufficiently by temporary controlled systemic hypotension, with or without the aid of temporary balloon occlusion of the main arterial feeder(s). Retrograde spread of sclerosant within the nidus that falls short of filling arterial feeders and their branches to normal brain tissue may then be possible. Angioarchitectural and hemodynamic considerations are addressed, as are the potential role and limitations of TRENSH in the management of cerebral pial AVMs. Future implementation of this new technique in some specific selected cases in which the anatomic configuration of the AVM and its draining veins might be favorable could prove to be a potentially useful addition to the armamentarium of AVM therapies, which currently includes microsurgery, radiosurgery, and transarterial embolotherapy. Experimental studies directed at assessing the feasibility of TRENSH before potential future clinical application seem justified.

Abstract

Despite widespread applications in biomedical research, the role of models and modeling is often controversial and ill understood. It is usual to find that fundamental definitions, axioms, and postulates used in the modeling process have become tacit assumptions. What is essential, however, is a clear vision of the fundamental principles of modeling. This is even more compelling for new and emerging interdisciplinary fields that use techniques from previously separate scientific disciplines. This article outlines and reviews the central nature and philosophy of modeling, the rules that govern it, and its underlying key integral relationship to the 'scientific method'. A comprehensive understanding of these issues is indispensable to successful research and meaningful progress in all facets of biomedicine.

Abstract

We assessed the feasibility of creating an experimental arteriovenous malformation model in swine by diverting and increasing blood flow through bilateral retia mirabilia. This was achieved by surgical formation of a large right-sided carotid-jugular fistula, in combination with endovascular occlusion of several neck arteries ipsilateral to the fistula. Using this technique, 11 of 13 swine demonstrated an acute-phase angiographic simulation of an arteriovenous malformation. There was rapid circulatory diversion from the left ascending pharyngeal artery ("feeder"), across both retia ("nidus"), and fast retrograde flow into the right ascending pharyngeal and common carotid arteries ("draining vein") toward the fistula. The relevant vascular anatomy of the swine head and neck is outlined, and steps in the construction of this arteriovenous malformation model are detailed.

Abstract

Current chemotherapies for brain glioblastoma do not achieve sufficient drug concentrations within tumors. Polymeric nanoparticles have useful physicochemical properties that make them promising as nanoparticle platforms for glioblastoma drug delivery. Poly[lactic-co-glycolic acid] (PLGA) nanoparticles encapsulating temozolomide (TMZ) could improve localized delivery and sustained drug release to glioblastomas.We investigated three different procedures to encapsulate TMZ within PLGA nanoparticles. We studied the biophysical features of optimized nanocarriers, including their size, shape, surface properties, and release characteristics of TMZ. We evaluated the antiproliferative and cytotoxic effects of TMZ-loaded PLGA nanoparticles on U87 MG glioblastoma cells.A single emulsion technique using a TMZ saturated aqueous phase produced nanoparticles ?200 nm in size allowing a maximal drug loading of 4.4% w/w of polymer. There was a bi-phasic drug release pattern, with 80% of TMZ released within the first 6 h. Nanoparticles accumulated in the cytoplasm after effective endocytosis. There was no significant difference in cytotoxic effect of TMZ encapsulated within PLGA nanoparticles and free TMZ.PLGA nanoparticles are not suitable as carriers of TMZ for glioblastoma drug delivery on account of the overall high IC50 values of glioblastoma cells to TMZ and poor loading and encapsulation efficiencies. Further biotechnological developments aimed at improving the loading of TMZ in PLGA nanoparticles or co-delivery of small molecule sensitizers to improve the response of human glioblastoma cells to TMZ are required for this approach to be considered and optimized for future clinical translation.

Trends in Performance Indicators of Neuroimaging Anatomy Research Publications: A Bibliometric Study of Major Neuroradiology Journal Output Over Four Decades Based on Web of Science DatabaseCLINICAL ANATOMYWing, L., Massoud, T. F.2015; 28 (1): 16-26

Abstract

Background An appreciation of normal intracranial anatomy allows optimal planning of trajectories necessary for safe and effective neuroendoscopy. Little information exists on displacement of the caudal brain relative to the skull upon head movement; this could have important implications for planning and performance of neuroendoscopic procedures. We used kinematic magnetic resonance imaging (MRI) studies to examine the morphometric displacement and changing anatomical relationships between the clivus and basal brain structures, intracranial vessels, and subarachnoid spaces.Patients We retrospectively analyzed 15 patients undergoing sagittal T2 kinematic MRI of the head and neck in modest flexion and extension. The angle between a horizontal axial reference plane and a line between the opisthion and the hard palate defined the degree of flexion and extension. We then measured in flexion and extension (1) the cervicomedullary angle (CMA), (2) displacement of the ventral surface of the brainstem (i.e., depth of the prepontine and premedullary cisterns), (3) total sagittal area of the combined suprasellar and ventral brainstem cisterns, and (4) the basilar tip to tuber cinereum distance.Results Relative to neutral head position, a mean extension angle of -15.8 degrees was achieved in all 15 patients, and a mean flexion angle of +9.9 degrees was achieved in 6 patients. The mean CMA was 146 degrees in flexion and 158 degrees in extension. The mean reduction in prepontine and premedullary cistern depth was 0.7 mm and 0.5 mm, respectively, upon flexion from extension. The combined area of suprasellar and ventral brainstem cisterns was minimally reduced from 402 mm2 in flexion to 399 mm2 in extension. The basilar tip did not move significantly from its position in flexion to extension, 5.3 mm to 5.2 mm respectively from the tuber cinereum.Conclusion Kinematic MRI shows minimal brainstem-to-clivus displacement even within minor physiological changes in head flexion. Importantly, these movements are small and there is no significant shift in the position of the basilar tip in modest flexion or extension. These results should be useful for presurgical planning of optimal patient positioning during neuroendoscopic procedures such as third ventriculostomy and the expanded endonasal transsphenoidal approach to the retroclival space.

Abstract

BACKGROUND:: The aqueduct of Sylvius (AsSylv) is a structure of increasing importance in neuroendoscopic procedures. However, there is currently no clear and adequate description of the normal anatomy of the AqSylv. OBJECTIVE:: To study in detail hitherto unavailable normal MRI morphometry and anatomical variants of the AqSylv. METHODS:: We retrospectively studied normal midsagittal T1-weighted 3T MR images in 100 patients. We measured widths of the AqSylv pars anterior, ampulla, pars posterior, narrowest point, and its length. We recorded angulation of the AqSylv relative to the third ventricle as multiple deviations of the long axis of the AqSylv from Talairach's bicommissural line. We statistically determined age- and gender-related changes in AqSylv morphometry using Pearson's correlation coefficient. We measured angulation of the AqSylv relative to the fourth ventricle and correlated this to the cervico-medullary angle (CMA, a surrogate for head position). RESULTS:: Patients were aged 13- 83 years (55:45, F:M). Mean morphometrics were: width of pars anterior (1.1 mm), ampulla (1.2 mm), pars posterior (1.4 mm), length (14.1 mm), narrowest point (0.9 mm), and angulation in relation to the third (26°) and fourth (18°) ventricles. Age correlated positively with width and negatively with length of the AqSylv. There was no correlation between AqSylv alignment relative to the foramen magnum, and the CMA. CONCLUSION:: Normative dimensions of the AqSylv in vivo are at variance with published cadaveric morphometrics. The AqSylv widens and shortens with cerebral involution. Awareness of these normal morphometrics is highly useful when stent placement is an option during aqueductoplasty. Reported data are valuable in guiding neuroendoscopic management of hydrocephalus and aqueductal stenosis.

Abstract

Arterial bleeding in the interpeduncular fossa is a dreaded complication of endoscopic third ventriculostomy (ETV). When the "safe zone" of the tuber cinereum (TC) is fenestrated, the basilar artery tip (BT) or its branches may be encountered below the third ventriclular floor. Major arterial injuries might be avoided by careful preoperative planning. We aimed to establish previously unavailable normal magnetic resonance imaging (MRI) and MR angiographic (MRA) morphometry and configuration of the BT and posterior cerebral artery P1 segments relative to the TC.We analyzed images of 82 patients with non-dilated ventricles (mean Evans' index 0.26), and lying in a neutral head position (mean cervico-medullary angle 141°). We cross-referenced axial MRAs with sagittal MRIs to measure distances of BT and P1 segments from the TC, and to classify the location of the BT in the interpeduncular and suprasellar cisterns. We correlated the sagittal areas of these cisterns and patients' ages with the TC-to-artery distances using regression analysis.The BT, right P1 and left P1 segments were a mean 4.9 mm, 5.5 mm, and 5.7 mm respectively from the TC. Seventy-four percent of BTs were anterior to the mammillary bodies. These distances and locations did not correlate with age (mean 53 years) or size of basal cisterns.The normal BT and P1 segments are anatomically close to the TC and potentially at risk during ETV in adults of all ages. The new morphometric data presented, along with cross-referencing of preoperative multiplanar images, could help reduce vascular complications during ETV.

Abstract

The circumventricular organs (CVOs) occupy seven midline locations around the ventricles. They contain specialized ependymal cells called tanycytes and have an incomplete blood-brain barrier (BBB). We hypothesized that appearances of the lesser known CVOs on contrast-enhanced MRI might lead to confusion in image interpretation whereby they might be mistaken for pathology-related abnormal contrast enhancement. We therefore assessed the normal appearances and prevalence of contrast enhancement of the CVOs on routine clinical brain MRI and reviewed the functional anatomy of the CVOs.We retrospectively reviewed sagittal and coronal pre- and post-contrast T1-weighted brain 3T MR images in 100 adult patients with normal findings. We assessed the presence of the median eminence (ME), neurohypophysis (NH), pineal gland (PG), subforniceal organ (SFO), organum vasculosum of the lamina terminalis (OVLT), subcommissural organ (SCO), and the area postrema (AP).The frequency of contrast enhancement of the seven CVOs was as follows: ME in 100 %, NH in 96 %, PG in 84 %, SFO in 1 %, OVLT in 34 %, SCO in 0 %, and AP in 2 %.The main CVOs (ME, NH, and PG) are well known and appreciated on brain imaging. However, there is a little awareness of the minor CVOs among neuroimagers. This is the first study of contrast enhancement prevalence of the SF, OV, SC, and AP on brain MRI. All the latter are small, faint, rarely visualized, and therefore not likely to cause misinterpretation with significant sources of pathology that cause breakdown of the BBB, such as tumor or inflammation.

Abstract

Asymmetric lacrimal flow occurs in females more than males. We hypothesised that the normal lacrimal drainage system (LDS) may show subtle left-rightasymmetry in morphometry when imaged on dacryocystography (DCG).We retrospectively reviewed 60 normal bilateral LDSs.Images were analysed for 7 parameters: (1) combined length of either the superioror inferior canaliculus plus common canaliculus, (2) angle of insertion of common canaliculus into lacrimal sac (LS), (3, 4) length and width of the LS, (5) length of thenasolacrimal duct (NLD), and (6, 7) width of proximal and distal NLD. We testedthe effect of independent variables (age, gender, and side) on each dependentvariable (length, width, or angle) using regression analysis. We used a Studentt-test for independent samples to statistically compare bilateral LDSs.Patient median age was 62 years, and male:female ratio was 27:73. Mean dimensions and angles for all LDSs were: (1) 14.5 mm, (2) 57°,(3) 11.6 mm, (4) 2.1 mm, (5) 20.7 mm, (6) 1.4 mm, and (7) 1.8 mm. No independent variable affected variation in length, width, or angle. No significant difference emerged between dimensions of right and left LDSs in both sexes.Conclusions: A degree of affective lateralisation in the brain is known to result inlacrimal flow asymmetry after mood manipulation. We show that this is not reflected in LDS anatomy. Moreover, our detailed morphometric data can aid in therapeuticplanning of LDS luminal procedures, especially when DCG images of one LDS are used as a road map for contralateral interventions.

Abstract

Digital subtraction sialography of the sublingual glands has not been reported previously, to our knowledge. We present a case series in which unintended digital subtraction sialography of the sublingual glands occurred during attempts at submandibular digital subtraction sialography. In four of the six cases, a mistaken diagnosis of severe sublingual gland sialectasis was made.Because of the unique histologic characteristics of the sublingual glands, knowledge of the technical aspects of sublingual duct cannulation and the relevant imaging anatomy is necessary to avoid image misinterpretation and clinical mismanagement.

The role of salivary duct morphology in the aetiology of sialadenitis: statistical analysis of sialographic featuresINTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERYHorsburgh, A., Massoud, T. F.2013; 42 (1): 124-128

Abstract

Morphologic characteristics of salivary ducts may contribute to stagnation of saliva. The authors hypothesized that some features might contribute to development of submandibular and parotid sialadenitis. 106 digital subtraction sialograms (DSS) were retrospectively reviewed for: degree of sialadenitis, length of Wharton's and Stensen's ducts (SD), and angle of Wharton's duct (WD) genu. Student's t test was used for independent samples to statistically compare normal and sialadenitis groups. The effect of independent variables (age, gender, side, degree of sialadenitis) on the dependent variable (length or angle) were tested using regression analysis. Submandibular duct sialadenitis was mild (67%), moderate (8%), or severe (25%); parotid duct sialadenitis was mild (57%), moderate (18%), or severe (25%). Mean length of normal WD was 58.2 mm, and 56.3 mm with sialadenitis. Mean length of normal SD was 52 mm, and 53 mm with sialadenitis. The mean angle of WD genu was 115° in normal ducts, and 119° with sialadenitis. None of the independent variables affected variation in length or angle. There were no statistical differences in duct length or measured angle between normal and sialadenitis groups. There is a wide variation in salivary duct morphology but this does not appear to be associated with the cause of sialadenitis.

Abstract

Idiopathic intracranial hypertension (IIH) is a condition of raised cerebrospinal fluid (CSF) pressure with normal ventricular size. Although the pathogenesis of IIH remains controversial, increased CSF formation may be important. We hypothesised that if increased CSF formation was an aetiologic factor, it might result in a macroscopic increase in size of the choroid plexus (CP).We retrospectively studied 50 patients with IIH. Total size of the CP was estimated on computed tomography (CT) venograms from the sum of axial areas measured at three locations. Results were compared with the CP load of 50 matched controls on post-contrast head CTs. Evans Index was measured to exclude ventriculomegaly. Results were analysed using a Student's t test for independent samples (p < 0.05), and the effect of ICP was tested on the dependent variable (area of CP) using regression analysis.There was no significant difference in the size of the CP glomus, total axial areas of the CP between IIH patients (183 mm(2)) and controls (178 mm(2)) and no correlation between the 'load' of CP and the degree of intracranial pressure (ICP) (R (2)< 0.02).If increased CSF formation is an aetiologic factor in IIH, this is not reflected in a corresponding raised 'load' of CP.

Abstract

Protrusions of fourth ventricular choroid plexus through the foramina of Luschka are called 'Bochdalek's flower basket' (BochFB). The bulbous terminal expansions (cornucopiae) extend into the cerebellopontine angle (CPA) cisterns. We studied and reviewed the normal imaging anatomy, morphometry and anatomical variants of BochFB.We retrospectively analysed normal brain imaging findings on axial pre- and post-contrast CT scans and enhanced axial T1-weighted MRIs of 200 patients. We assessed BochFB for: (a) calcification, (b) lateral extension, (c) enhancement pattern, (d) cornucopiae shape, (e) symmetry and (f) proximity to tortuous vertebral arteries and morphometry of cornucopiae size and length of BochFB limbs.BochFB calcification was found in 38 % of patients aged over 51 years. Lateral extension of BochFB into the CPA cistern was prominent in 75 % on CT and 96 % on MRI. The mean length of these extensions was 23.6 mm. BochFB enhanced strongly in 47 % on CT and 66 % on MRI. The BochFB cornucopiae were bulbous in 51 % on CT and 54 % on MRI. The mean width of bulbous cornucopiae was 3.5 mm. Bilateral BochFB symmetry was found in 71 % on CT and 80 % on MRI. Six to 8 % of tortuous left vertebral arteries were close to BochFB.The cornucopiae are particularly well demonstrated on post-contrast MRI. However several sources of error in image interpretation may arise when imaging the normal BochFB on routine head CT and MRI. Difficulties in analysis arise especially on CT because of physiologic calcification, asymmetry, and the bulbous cornucopiae being mistaken for aneurysms.

Abstract

Up-regulation of the folding machinery of the heat-shock protein 90 (Hsp90) chaperone protein is crucial for cancer progression. The two Hsp90 isoforms (? and ?) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(?/?)/cochaperone p23 interactions, we developed a dual-luciferase (Renilla and Firefly) reporter system for high-throughput screening (HTS) and monitoring the efficacy of Hsp90 inhibitors in cell culture and live mice. HTS of a 30,176 small-molecule chemical library in cell culture identified a compound, N-(5-methylisoxazol-3-yl)-2-[4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylthio]acetamide (CP9), that binds to Hsp90(?/?) and displays characteristics of Hsp90 inhibitors, i.e., degradation of Hsp90 client proteins and inhibition of cell proliferation, glucose metabolism, and thymidine kinase activity, in multiple cancer cell lines. The efficacy of CP9 in disrupting Hsp90(?/?)/p23 interactions and cell proliferation in tumor xenografts was evaluated by non-invasive, repetitive Renilla luciferase and Firefly luciferase imaging, respectively. At 38 h posttreatment (80 mg/kg × 3, i.p.), CP9 led to selective disruption of Hsp90?/p23 as compared with Hsp90?/p23 interactions. Small-animal PET/CT in the same cohort of mice showed that CP9 treatment (43 h) led to a 40% decrease in (18)F-fluorodeoxyglucose uptake in tumors relative to carrier control-treated mice. However, CP9 did not lead to significant degradation of Hsp90 client proteins in tumors. We performed a structural activity relationship study with 62 analogs of CP9 and identified A17 as the lead compound that outperformed CP9 in inhibiting Hsp90(?/?)/p23 interactions in cell culture. Our efforts demonstrated the power of coupling of HTS with multimodality molecular imaging and led to identification of Hsp90 inhibitors.

Abstract

Estrogen receptor (ER) biology reflects the actions of estrogens through the two receptors, ER? and ER?, although little is known regarding the preference for formation of ER homo- vs. heterodimers, and how this is affected by the level of ligand occupancy and preferential ligand affinity for one of the ER subtypes. In this report, we use a split optical reporter-protein complementation system to demonstrate the physical interaction between ER? and ER? in response to different ER ligands in cells and, for the first time, by in vivo imaging in living animals. The genetically encoded reporter vectors constructed with the ligand-binding domains of ER? and ER?, fused to split firefly or Renilla luciferase (Fluc or hRluc) fragments, were used for this study. This molecular proteomic technique was used to detect ER?/ER? or ER?/ER? homodimerization, or ER?/ER? heterodimerization induced by ER subtype-selective and nonselective ligands, and selective ER modulators (SERM), as well as in dimers in which one mutant monomer was unable to bind estradiol. The SERM-bound ER? and ER? form the strongest dimers, and subtype-preferential homodimerization was seen with ER?-selective ligands (methyl piperidino pyrazole/propyl pyrazole triol) and the ER?-selective ligands (diarylpropionitrile/tetrahydrochrysene/genistein). We also demonstrated that a single ligand-bound monomer can form homo- or heterodimers with an apo-monomer. Xenografts of human embryonic kidney 293T cells imaged in living mice by bioluminescence showed real-time ligand induction of ER?/ER? heterodimerization and reversal of dimerization upon ligand withdrawal. The results from this study demonstrate the value of the split luciferase-based complementation system for studying ER-subtype interactions in cells and for evaluating them in living animals by noninvasive imaging. They also probe what combinations of ER? and ER? dimers might be the mediators of the effects of different types of ER ligands given at different doses.

Abstract

Gold has been used as a therapeutic agent to treat a wide variety of rheumatic diseases including psoriatic arthritis, juvenile arthritis, and discoid lupus erythematosus. Although the use of gold has been largely superseded by newer drugs, gold nanoparticles are being used effectively in laboratory based clinical diagnostic methods while concurrently showing great promise in vivo either as a diagnostic imaging agent or a therapeutic agent. For these reasons, gold nanoparticles are therefore well placed to enter mainstream clinical practice in the near future. Hence, the present review summarizes the chemistry, pharmacokinetics, biodistribution, metabolism, and toxicity of bulk gold in humans based on decades of clinical observation and experiments in which gold was used to treat patients with rheumatoid arthritis. The beneficial attributes of gold nanoparticles, such as their ease of synthesis, functionalization, and shape control are also highlighted demonstrating why gold nanoparticles are an attractive target for further development and optimization. The importance of controlling the size and shape of gold nanoparticles to minimize any potential toxic side effects is also discussed.

Bioluminescence resonance energy transfer (BRET) imaging of protein-protein interactions within deep tissues of living subjectsPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICADragulescu-Andrasi, A., Chan, C. T., De, A., Massoud, T. F., Gambhir, S. S.2011; 108 (29): 12060-12065

Abstract

Identifying protein-protein interactions (PPIs) is essential for understanding various disease mechanisms and developing new therapeutic approaches. Current methods for assaying cellular intermolecular interactions are mainly used for cells in culture and have limited use for the noninvasive assessment of small animal disease models. Here, we describe red light-emitting reporter systems based on bioluminescence resonance energy transfer (BRET) that allow for assaying PPIs both in cell culture and deep tissues of small animals. These BRET systems consist of the recently developed Renilla reniformis luciferase (RLuc) variants RLuc8 and RLuc8.6, used as BRET donors, combined with two red fluorescent proteins, TagRFP and TurboFP635, as BRET acceptors. In addition to the native coelenterazine luciferase substrate, we used the synthetic derivative coelenterazine-v, which further red-shifts the emission maxima of Renilla luciferases by 35 nm. We show the use of these BRET systems for ratiometric imaging of both cells in culture and deep-tissue small animal tumor models and validate their applicability for studying PPIs in mice in the context of rapamycin-induced FK506 binding protein 12 (FKBP12)-FKBP12 rapamycin binding domain (FRB) association. These red light-emitting BRET systems have great potential for investigating PPIs in the context of drug screening and target validation applications.

Abstract

Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing larger Raman signals through surface-enhanced Raman scattering. Because we are developing these particles for use as targeted molecular imaging agents, we examined the acute toxicity and biodistribution of core polyethylene glycol (PEG)-ylated R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by macrophages in the liver and spleen (that is, the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks after administration. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical, or cardiovascular parameters for 2 weeks. Because we are designing targeted PEG-R-Si-Au-NPs (for example, PEG-R-Si-Au-NPs labeled with an affibody that binds specifically to the epidermal growth factor receptor) to detect colorectal cancer after administration into the bowel lumen, we tested the toxicity of the core nanoparticle after administration per rectum. We observed no significant bowel or systemic toxicity, and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs and their toxicity when carrying the targeting moiety, the results presented here support the idea that PEG-R-Si-Au-NPs can be safely used in living subjects, especially when administered rectally.

Abstract

Polyethylene glycol (PEG)ylated Raman-active gold nanoparticles (PEG-R-AuNPs) consist of an interchangeable Raman organic molecule layer held onto a gold nanocore by a silica shell. PEG-R-AuNPs have been shown preclinically to increase the sensitivity and specificity of Raman spectroscopy, with picomolar sensitivity and multiplexing capabilities. Although clinical trials are being designed to use functionalized PEG-R-AuNPs in various applications (e.g., to target dysplastic bowel lesions during colonoscopy), the effects of these nanoparticles on human cells remain unknown. The occurrence and mechanisms underlying any potential cytotoxicity induced by these nanoparticles (0-1000 PEG-R-AuNPs/cell) are investigated in immortalized human HeLa and HepG2 cell lines at several time points (0-48 h) after exposure. Using fluorometric assays, cell viability (MTT), reactive oxygen species (ROS) generation (dichlorofluorescein diacetate), protein oxidation (protein carbonyl content), and total cellular antioxidant concentrations the concentrations (metmyoblobin-induced oxidation of ABTS) are assessed. Analysis of lipid oxidation using an enzyme immunoassay (8-isoprostane concentrations), gene expression of antioxidant enzymes using quantitative reverse transcription polymerase chain reactions, and the intracellular location of PEG-R-AuNPs using transmission electron microscopy is also undertaken. PEG-R-AuNPs cause no cytotoxicity in either HeLa or HepG2 cells in the acute setting as ROS generation is balanced by antioxidant enzyme upregulation. Following prolonged exposures (48 h) at relatively high concentrations (1000 PEG-R-AuNPs/cell), nanoparticles are found within vesicles inside cells. Under these conditions, a minimal amount of cytotoxicity is seen in both cell lines owing to increases in cellular oxidative stress, most likely due to ROS overwhelming the antioxidant defenses. Evidence of oxidative stress-induced damage includes increased lipid and protein oxidation. Although further in vivo toxicity studies are necessary, these initial encouraging results show that PEG-R-AuNPs cause minimal toxicity in human cells in the acute setting, which bodes well for potential future applications of these nanoparticles in living subjects.

Abstract

The cytoplasmic Myc protein (c-Myc) regulates various human genes and is dysregulated in many human cancers. Phosphorylation mediates the protein activation of c-Myc and is essential for the function of this transcription factor in normal cell behavior and tumor growth. To date, however, the targeting of Myc as a therapeutic approach for cancer treatment has been achieved primarily at the nonprotein level. We have developed a molecular imaging sensor for noninvasive imaging of c-Myc activity in living subjects using a split Firefly luciferase (FL) complementation strategy to detect and quantify the phosphorylation-mediated interaction between glycogen synthase kinase 3beta (GSK3beta) and c-Myc. This sensor system consists of two fusion proteins, GSK 35-433-CFL and NFL-c-Myc, in which specific fragments of GSK3beta and c-Myc are fused with C-terminal and N-terminal fragments of the split FL, respectively. The sensor detects phosphorylation-specific GSK3beta-c-Myc interaction, the imaging signal of which correlates with the steady-state and temporal regulation of c-Myc phosphorylation in cell culture. The sensor also detects inhibition of c-Myc activity via differential pathways, allowing noninvasive monitoring of c-Myc-targeted drug efficacy in intact cells and living mice. Notably, this drug inhibition is detected before changes in tumor size are apparent in mouse xenograft and liver tumor models. This reporter system not only provides an innovative way to investigate the role of functional c-Myc in normal and cancer-related biological processes, but also facilitates c-Myc-targeted drug development by providing a rapid quantitative approach to assessing cancer response to therapy in living subjects.

Abstract

The use of regulated gene expression systems is important for successful gene therapy applications. In this study, ligand-induced structural change in the estrogen receptor (ER) was used to develop a novel ER intramolecular folding-based transcriptional activation system. The system was studied using ER-variants of different lengths, flanked on either side by the GAL4-DNA-binding domain and the VP16-transactivation domain (GAL4(DBD)-ER-VP16). The ER ligands of different types showed efficient ligand-regulated transactivation. We also characterized a bidirectional transactivation system based on the ER and demonstrated its utility in titrating both reporter and therapeutic gene expression. The ligand-regulated transactivation system developed by using a mutant form of the ER (G521T, lacking affinity for the endogenous ligand 17beta-estradiol, whereas maintaining affinity for other ligands) showed efficient activation by the ligand raloxifene in living mice without significant interference from the circulating endogenous ligand. The ligand-regulated transactivation system was used to test the therapeutic efficiency of the tumor suppressor protein p53 in HepG2 (p53(+/+)) and SKBr3 (p53(-/-)/mutant-p53(+/+)) cells in culture and tumor xenografts in living mice. The multifunctional capabilities of this system should be useful for gene therapy applications, to study ER biology, to evaluate gene regulation, ER ligand screening, and ER ligand biocharacterization in cells and living animals.

Abstract

Prostate cancer remains an important and growing health problem. Advances in imaging of prostate cancer may help to achieve earlier and more accurate diagnosis and treatment. We review the various strategies using reporter genes for molecular imaging of prostate cancer. These approaches are emerging as valuable tools for monitoring gene expression in laboratory animals and humans. Further development of more sensitive and selective reporters, combined with improvements in detection technology, will consolidate the position of reporter gene imaging as a versatile method for understanding of intracellular biological processes and the underlying molecular basis of prostate cancer, as well as potentially establishing a future role in the clinical management of patients afflicted with this disease.

Abstract

Networks of protein interactions mediate cellular responses to environmental stimuli and direct the execution of many different cellular functional pathways. Small molecules synthesized within cells or recruited from the external environment mediate many protein interactions. The study of small molecule-mediated interactions of proteins is important to understand abnormal signal transduction pathways in cancer and in drug development and validation. In this study, we used split synthetic renilla luciferase (hRLUC) protein fragment-assisted complementation to evaluate heterodimerization of the human proteins FRB and FKBP12 mediated by the small molecule rapamycin. The concentration of rapamycin required for efficient dimerization and that of its competitive binder ascomycin required for dimerization inhibition were studied in cell lines. The system was dually modulated in cell culture at the transcription level, by controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis factor alpha, and at the interaction level, by controlling the concentration of the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera. This split reporter system can be used to efficiently screen small molecule drugs that modulate protein-protein interactions and also to assess drugs in living animals. Both are essential steps in the preclinical evaluation of candidate pharmaceutical agents targeting protein-protein interactions, including signaling pathways in cancer cells.

Abstract

A Doppler sonographic guidewire was used to monitor incremental changes in draining vein (DV) flow during endovascular occlusion of a complex vertebral arteriovenous fistula (AVF) in a patient with neurofibromatosis type 1. Transvenous monitoring of average peak velocity (APV) and the maximum-minus-minimum peak velocity (MxPV-MnPV) demonstrated a progression from a highly pulsatile, fast flow before embolization to a nonpulsatile, slow flow indicating a successful occlusion of the AVF (hemodynamic endpoint of treatment). Prior to this, apparent angiographic occlusion of the AVF was thought to signify a successful endpoint; however, persistently elevated values for APV and MxPV-MnPV in the DV signalled the presence of an additional contralateral arterial contribution. Transvenous monitoring of flow velocity appears to be ideally suited to establishing a hemodynamic endpoint of embolotherapy in the presence of complex arteriovenous shunting, as may occur with the vasculopathy of neurofibromatosis.

Abstract

The size of intracranial aneurysms is the only characteristic shown to correlate with their rupture. However, the critical size for rupture has varied considerably among previous accounts and remains a point of controversy. Our goal was to identify statistically significant clinical and morphological factors predictive of the occurrence of rupture and aneurysm size in patients referred for endovascular treatment. We retrospectively recorded the following factors from 74 patients who presented with ruptured (40) or unruptured (34) aneurysms: aneurysm morphology (uni/multilobulated), location (anterior/posterior), maximum diameter, diameter of the neck, and the patient's age and sex. We performed stepwise discriminant, and stepwise and logistic regression analysis to identify factors predicting rupture and the size of the aneurysm at rupture. The mean diameter of the ruptured aneurysms was 11.9+/-6.3 mm, range 3.0-33.0 mm, and that of the unruptured aneurysm 13.5+/-5.8 mm, range 5.0-30 mm. Stepwise discriminant analysis identified aneurysm morphology (P < 0.001) and location in the intracranial circulation (P < 0.001) as statistically significant factors in predicting rupture. Stepwise regression analysis revealed that aneurysm morphology and the size of the neck were predictors of aneurysm size at rupture.

Abstract

To explore the feasibility of using a theoretical computational model to simulate the risk of spontaneous arteriovenous malformation (AVM) haemorrhage.Data from 12 patients were collected from a prospective databank which documented the angioarchitecture and morphological characteristics of the AVM and the feeding mean arterial pressure (FMAP) measured during initial superselective angiography prior to any treatment. Using the data, a computational model of the cerebral circulation and the AVM was constructed for each patient (patient-specific model). Two model risk (Risk(model)) calculations (haemodynamic- and structural-weighted estimates) were performed by using the patient-specific models. In our previously developed method of haemodynamic-weighted estimate, Risk(model) was calculated with the simulated intranidal pressures related to its maximal and minimal values. In the method of structural-weighted estimate developed and described in this paper, the vessel mechanical properties and probability calculation were considered in more detail than in the haemodynamic-weighted estimate. Risk(model) was then compared to experimentally determined risk which was calculated using a statistical method for determining the relative risk of having initially presented with AVM haemorrhage, termed Risk(exp).The Risk(model) calculated by both haemodynamic- and structural-weighted estimates correlated with experimental risks with chi2 = 6.0 and 0.64, respectively. The risks of the structural-weighted estimate were more correlated to experimental risks.Using two different approaches to the calculation of AVM haemorrhage risk, we found a general agreement with independent statistical estimates of haemorrhagic risk based on patient data. Computational approaches are feasible; future work can focus on specific pathomechanistic questions. Detailed patient-specific computational models can also be developed as an adjunct to individual patient risk assessment for risk-stratification purposes.

Abstract

Complete intracranial aneurysmal occlusion by endovascular techniques is required for successful treatment and is presumably influenced by several parameters. The purpose of this study was to investigate whether operator experience and angiographic characteristics of intracranial aneurysms correspond to the degree of endovascular occlusion in the period immediately after treatment with Guglielmi detachable coils (GDCs).Pre- and posttreatment angiograms of 72 patients undergoing GDC treatment were reviewed retrospectively. The following angiographic characteristics of the aneurysms were evaluated: largest diameter of the sac, volume, neck size, shape, type, cerebrovascular site, surroundings, and likely direction of aneurysmal inflow as judged by a score developed by measuring aneurysm/parent artery angulation. The chronological sequence in which the aneurysms were treated was used as a measure of operator experience. A chi2-test was used to identify parameters that correlated with outcomes of total (100%) or partial (<100%) occlusion. A multivariate analysis was used to determine the factors most predictive of aneurysmal occlusion at therapy.Parameters that correlated with the unsatisfactory result of partial occlusion were large aneurysmal diameter, volume, and neck size, more direct inflow (ie, increasingly obtuse aneurysm/parent artery angulation), and early chronological presentation in the series. The three factors most predictive of partial occlusion were large aneurysmal diameter, more direct inflow, and early chronological order of treatment.Several morphologic features of aneurysms were identified to help predict the immediate outcome of occlusion with GDCs. This study underscores the existence of a steep learning curve associated with GDC use in treating aneurysms and the importance of operator experience in achieving optimal therapeutic results.

Abstract

Summary: Ion implantation and protein-coatings were utilized to alter the surface properties (endothelial cellular adhesion) and enhance the thrombogenicity of Guglielmi detachable coils (GDCs) for endovascular treatment of cerebral aneurysms. These modified GDCs were compared with standard GDCs in the treatment of experimental swine aneurysms. Standard GDCs and ion-implanted protein coated GDCs were used to treat 32 aneurysms in 16 swine. GDCs were coated with either proteins, collagen (n=5), vitronectin (n=4), fibrinogen (Fn=3), laminin (n=2), or fibronectin (n=2) and underwent Ne(+) or He(+) implantation with a fluence of 1 x 10(14--) 10(15) ions/cm(2) at an energy of 150 keV. Bilateral experimental swine aneurysms were embolized with standard GDCs (n=16) on one side and with ion-implanted proteincoated GDCs (n=16; total) on the other side. The necks of aneurysms were evaluated macroscopically and histopathologically at autopsy using day 14 posttreatment specimens. Greater fibrous coverage of the necks of aneurysms were observed in the ion-implanted coil group. The results of this experimental study indicate that Ion implantation combined with protein coating of GDCs improved cellular adhesion and proliferation. Future application of this technology may provide early wound healing at the necks of embolized widenecked cerebral aneurysms.

Abstract

Intracranial aneurysms occur frequently with the risk of major damage. Neurosurgery or endovascular techniques can be used for treatment. Current techniques are not well adapted for aneurysms with a wide implantation (or neck). The aim of this experimental work was to study a technique for treating aneurysms which can be used for wide neck aneurysms. A metal stent is implanted facing the neck of the aneurysm to allow occlusion. In the first part of the study, the stent was inserted alone. Ten aneurysms were created surgically in five dogs. The stents were positioned facing seven of the ten aneurysms. The stent led to immediate occlusion of the aneurysm in six of the cases. One aneurysm remained patent despite the correct position of the stent. One dog developed secondary thrombosis of the carotid. Three dogs have been followed for sixty days after insertion of the stent. Two aneurysms thrombosed and one was patent. Since these results were less than satisfactory, a second part of the study was undertaken to cover the stent with a fragment of the autologous vein. Results in five aneurysms, evaluated three and eight weeks after treatment, showed partial or total repermeabilization of the aneurysms. In the third part of the study, we associated stents and detachable coils. Twelve aneurysms of the carotid artery in pigs were thrombosed and two aneurysms were completely occluded after stent implantation. In the nine other cases, the aneurysms were completely occluded after stent implantation. In the nine other cases, the aneurysms remained patent despite the stent and treatment was then completed with a coil. Six of the animals have been followed for thirteen weeks. One carotid artery thrombosed. In the five other cases, the carotid arteries were patent and the aneurysms were occluded at the control angiogram. Histology results showed the presence of a fibromuscular endothelialized neointima at the neck of the aneurysm in four of the five cases. The technique described here could be proposed for the treatment of wide-neck aneurysms implanted low on the carotid artery in man. Improvements should render the system more flexible.

Abstract

Stroke is the third leading cause of death and the leading cause of long-term disability in the United States. Although a host of genetic, biochemical, physiological, anatomic, and histological factors have been implicated, to varying degrees, in the pathogenesis of stroke, biophysical factors are believed to play a significant role in the development, diagnosis, and therapy of stroke. The purpose of this review article is to identify, describe, and illustrate these causes and biophysical and hemodynamic mechanisms predisposing a person to stroke, which often form the basis for novel methods of diagnosis and therapy.This mini-review begins by describing the physical principles that govern the flow of blood through normal and stenosed carotid artery bifurcations. In addition to the tortuosity, curvature, and tensile forces of the carotid artery bifurcation, the effects of biophysical phenomena from flowing blood such as viscous forces, pressure forces, velocity, kinetic energy, momentum, impulse, shear stress, and vibrational displacements exerted by the flowing blood on the vessel wall are conducive to abnormal flow behavior and patterns, degrading the vessel wall and creating the potential for stroke.Recent advances in the treatment of stroke are based on increasing knowledge of its underlying biophysical mechanisms, as well as on better-publicized advances in imaging instrumentation and procedures for the management and treatment of patients.

Abstract

Biomathematical models of intracranial aneurysms can provide qualitative and quantitative information on stages of aneurysm development through elucidation of biophysical interactions and phenomena. However, most current aneurysm models, based on Laplace's law, are renditions of static, linearly elastic spheres. The primary goal of this study is to: 1. develop a nonlinear constitutive quasi-static model and 2. derive an expression for the critical size/pressure of an aneurysm, with subsequent applications to clinical data. A constitutive model of an aneurysm, based on experimental data of tissue specimens available in the literature, was incorporated into a time-dependent set of equations describing the dynamic behavior of a saccular aneurysm in response to pulsatile blood flow. The set of differential equations was solved numerically, yielding mathematical expressions for aneurysm radius and pressure. This model was applied to clinical data obtained from 24 patients presenting with ruptured aneurysms. Aneurysm development and eventual rupture exhibited an inverse relationship between aneurysm size and blood pressure. In general, the model revealed that rupture becomes highly probable for an aneurysm diameter greater than 2.0 mm and a systemic blood pressure greater than 125 mmHg. However, an interesting observation was that the critical pressure demonstrated a minimal sensitivity to the critical radius, substantiating similar clinical and experimental observations that blood pressure was not correlated, to any degree, with aneurysm rupture. Undulations in the aneurysm wall, presented by irregular multilobulated morphologies, could play an important role in aneurysm rupture. However, due to the large variation in results, more extensive studies will be necessary for further evaluation and validation of this model.

Abstract

Complete anatomic obliteration remains difficult to achieve with endovascular treatment of wide-necked aneurysms using Guglielmi detachable platinum coils (GDCs). Ion implantation is a physicochemical surface modification process resulting from the impingement of a high-energy ion beam. Ion implantation and protein coating were used to alter the surface properties (thrombogenicity, endothelial cellular migration, and adhesion) of GDCs. These modified coils were compared with standard GDCs in the treatment of experimental swine aneurysms.In an initial study, straight platinum coils were used to compare the acute thrombogenicity of standard and modified coils. Modified coils were coated with albumin, fibronectin, or collagen and underwent Ne+ ion implantation at a dose of 1 x 10(15) ions/cm2 and an energy of 150 keV. Coils were placed in common iliac arteries of 17 swine for 1 hour, to evaluate their acute interactions with circulating blood. In a second study, GDCs were used to treat 34 aneurysms in an additional 17 swine. GDCs were coated with fibronectin, albumin, collagen, laminin, fibrinogen, or vitronectin and then implanted with ions as described above. Bilateral experimental swine aneurysms were embolized with standard GDCs on one side and with ion-implanted, protein-coated GDCs on the other side. The necks of aneurysms were evaluated macroscopically at autopsy, by using post-treatment Day 14 specimens. The dimensions of the orifice and the white fibrous membrane that covered the orifice were measured as the fibrous membrane to orifice proportion. Histopathological evaluation of the neck region was performed by light microscopy and scanning electron microscopy.Fibronectin-coated, ion-implanted coils showed the greatest acute thrombogenicity (average thrombus weight for standard coils, 1.9 +/- 1.5 mg; weight for fibronectin-coated coils, 8.6 +/- 6.2 mg; P < 0.0001). By using scanning electron microscopy, an intensive blood cellular response was observed on ion-implanted coil surfaces, whereas this was rare with standard coils. At Day 14, greater fibrous coverage of the necks of aneurysms was observed in the ion-implanted coil group (mean fibrous membrane to orifice proportion of 69.8 +/- 6.2% for the ion-implanted coil group, compared with 46.8 +/- 15.9% for the standard coil group; P = 0.0143).The results of this preliminary experimental study indicate that ion implantation combined with protein coating of GDCs improved cellular adhesion and proliferation. Future application of this technology may provide early wound healing at the necks of embolized, wide-necked, cerebral aneurysms.

Abstract

The bifurcation of the common femoral artery (CFA) into superficial and profunda femoris arteries (PFA) and the branching pattern of the PFA are subject to considerable normal anatomical variation. These variation patterns were assessed on normal lower limb angiograms of 94 adult patients. The main pattern (in 81% of patients) consisted of both medial and lateral circumflex arteries arising directly from a PFA situated lateral or posterolateral to the femoral artery. Previous studies of arterial variations in this region and the relevant embryology are reviewed. Relevance to angiographic procedures of the lower limb is discussed.

Abstract

The propensity of intracranial arteriovenous malformations (AVMs) to hemorrhage is correlated significantly with their hemodynamic features. Biomathematical models offer a theoretical approach to analyse complex AVM hemodynamics, which otherwise are difficult to quantify, particularly within or in close proximity to the nidus. Our purpose was to investigate a newly developed biomathematical AVM model based on electrical network analysis in which morphological, biophysical, and hemodynamic characteristics of intracranial AVMs were replicated accurately. Several factors implemented into the model were altered systematically to study the effects of a possible wide range of normal variations in AVM hemodynamic and biophysical parameters on the behavior of this model and its fidelity to physiological reality. The model represented a complex, noncompartmentalized AVM with four arterial feeders, two draining veins, and a nidus consisting of 28 interconnected plexiform and fistulous components. Various clinically-determined experimentally-observed, or hypothetically-assumed values for the nidus vessel radii (plexiform: 0.01 cm-0.1 cm; fistulous: 0.1 cm-0.2 cm), mean systemic arterial pressure (71 mm Hg-125 mm Hg), mean arterial feeder pressures (21 mm Hg-80 mm Hg), mean draining vein pressures (5 mm Hg-23 mm Hg), wall thickness of nidus vessels (20 microns-70 microns), and elastic modulus of nidus vessels (1 x 10(4) dyn/cm2 to 1 x 10(5) dyn/cm2) were used as normal or realistic ranges of parameters implemented in the model. Using an electrical analogy of Ohm's law, flow was determined based on Poiseuille's law given the aforementioned pressures and resistance of each nidus vessel. Circuit analysis of the AVM vasculature based on the conservation of flow and voltage revealed the flow rate through each vessel in the AVM network. An expression for the risk of AVM nidus rupture was derived based on the functional distribution of the critical radii of component vessels. The two characteristics which were used to judge the fidelity of the theoretical performance of the AVM model against the physiological one of human AVMs were total volumetric flow through the AVM (< or = 900 ml/min), and its risk of rupture (< 100%). Applying these criteria, a series of 216 (out of 260) AVM models using different combinations of these hemodynamic and biophysical parameters resulted in a physiologically-realistic conduct of the model (yielding a total flow through the AVM model varying from 449.9 ml/min to 888.6 ml/min, and a maximum risk of rupture varying from 26.4 to 99.9%). The described novel biomathematical model characterizes the transnidal and intranidal hemodynamics of an intracranial AVM more accurately than previously possible. A wide range of hemodynamic and biophysical parameters can be implemented in this AVM model to result in simulation of human AVMs with differing characteristics (e.g. low-flow and high-flow AVMs). This experimental model should serve as a useful research tool for further theoretical investigations of a variety of intracranial AVMs and their hemodynamic sequelae.

Abstract

To study the effects of single-dose radiation on the porcine rete mirabile, a tangle of microvessels that mimics human arteriovenous malformations of the brain.Eight retia mirabilia received a single dose of radiation under stereotactic location with digital angiography and CT. The following doses were applied: 20, 30, 40, 50, 60, 70, 80, and 90 Gy. The animals were followed up for a period of 7 months. Findings at neurologic examination, serial angiography, and histopathologic examination were analyzed.Progressive occlusion as observed by angiography corresponded to the histopathologic finding of intimal hyperplasia; that is, marked thickening of the vessel wall, progressing to occlusion of the vascular lumen, and associated thrombosis. A direct dose response was noted for these changes. Neurologic findings were related to the dose distribution and to histologic findings in structures adjacent to the rete mirabile.The rete mirabile is an excellent model by which to study the radiologic and histologic effects of single-dose radiation to the microvasculature of the central nervous system.

Abstract

The technical feasibility of selective intranidal endovascular occlusion of experimental arteriovenous malformations with detachable superfine platinum electrodes was assessed in a swine model. The delivery and release of electrodes were performed within normal carotid retia mirabilia, the faster-flowing nidus (bilateral retia) of a carotid-jugular fistula-type model of an arteriovenous malformation, and a small-caliber H-type direct arteriovenous fistula. Controllable atraumatic placement of the electrodes was possible deep within each rete and in the middle of the fistula. The devices were soft and flexible, allowing them to conform to the tight turns and branches of rete vessels. Marked diminution of flow was achieved by release of multiple devices within each rete. Migration of the electrode occurred when detached within the larger-caliber arteriovenous fistula. The main advantages of this technique appear to be the controlled delivery and assured release of an occlusive radiopaque embolic agent within the nidus.

Abstract

A Doppler guidewire was used to monitor progressive changes in draining vein flow parameters during experimental embolotherapy in a swine arteriovenous malformation (AVM) model.A microcatheter was positioned superselectively in the main arterial feeder and main draining vein in each of 10 AVM models in swine. With use of the Doppler guidewire, preembolization arterial and venous average peak velocities (APVs) and pulsatility indices were recorded. The device was left in the draining vein during transarterial particulate (in 8 swine) or liquid adhesive (in 2 swine) embolization, and continuous transvenous flow during and after treatment was monitored. Periembolization Doppler flow parameters were correlated qualitatively with angiographic changes in the nidus.Preembolization draining vein flow was pulsatile, with a mean APV of 38.9 +/- 13.7 cm/s. After embolization, this changed significantly to a less pulsatile or nonpulsatile pattern, with a lower mean APV of 9.2 +/- 4.9 cm/s (P = .0001). A novel expression, the maximum minus the minimum peak velocity (MxPV-MnPV), was used in evaluating the transvenous Doppler spectra. This was reduced significantly after embolization from a mean of 11.1 +/- 3.5 cm/s to 6.7 +/- 2.5 cm/s (P = .0025). Objective periembolization hemodynamic changes were detected in the draining veins earlier than the visually subjective angiographic changes within the nidus.Transvenous Doppler guidewire assessment of two parameters, APV and MxPV-MnPV, is useful in the hemodynamic evaluation of experimental arteriovenous shunting and may be used for future objective and quantitative monitoring during endovascular AVM embolotherapy.

Abstract

Increased resistance in the venous drainage of intracranial arteriovenous malformations (AVMs) may contribute to their increased risk of hemorrhage. Venous drainage impairment may result from naturally occurring stenoses/occlusions, or if draining veins (DVs) undergo occlusion before feeding arteries during surgical removal, or after surgery in the presence of "occlusive hyperemia." We employed a detailed biomathematical AVM model using electrical network analysis to investigate theoretically the hemodynamic consequences and the risk of AVM rupture due to venous drainage impairment.The AVM model consisted of a noncompartmentalized nidus with 28 vessels (24 plexiform components and 4 fistulous components), 4 arterial feeders, and 2 DVs. An expression for the risk of AVM nidus rupture was derived on the basis of functional distribution of the critical radii of component vessels. Risk was calculated from biomathematical simulations of volumetric flow rate with both DVs patent and for four stages of venous drainage obstruction: (1) 25%, (2) 50%, (3) 75%, and (4) 100%. Each stage of occlusion was applied to each DV while the other DV was patent and then to the patent DV while the other DV was totally occluded.For flow through the AVM when both DVs were unobstructed, the baseline risk of AVM nidus rupture ranged from 4.4% to 91.2%. Theoretical rupture occurred in nidus components proximal to the DVs when the risk exceeded 100%, as was observed with the obstruction of DV1 and a patent DV2. The ranges for risk of rupture across the nidus for the four stages were (1) 4.7% to 90.5%, (2) 5.9% to 86.9%, (3) 0% to 98.4%, and (4) 0% to 106.3%, respectively. Rupture was observed for an 86% occlusion of DV1 (ie, the DV fed by the intranidal fistula) and DV2 patent, primarily because of the dramatic shift in the hemodynamic burden toward the weaker plexiform nidus vessels.On theoretical grounds, venous drainage impairment was predictive of AVM nidus rupture and was strongly dependent on AVM morphology (presence of intranidal fistulas and their spatial relation to DVs) and hemodynamics. Specifically, stenosis/occlusion of a high-flow DV induces a rapid redistribution of blood into the weak plexiform vessels of the opposing region of the nidus, causing a hemodynamic overload and an increased risk of rupture. These findings should be carefully considered among all factors affecting the natural history of intracranial AVMs and the mechanisms implicated in their spontaneous rupture. They may also provide a theoretical rationale for some of the hemorrhagic complications that occur during and after surgical treatment.

Abstract

Hemodynamics play a significant role in the propensity of intracranial arteriovenous malformations (AVMs) to hemorrhage and in influencing both therapeutic strategies and their complications. AVM hemodynamics are difficult to quantitate, particularly within or in close proximity to the nidus. Biomathematical models represent a theoretical method of investigating AVM hemodynamics but currently provide limited information because of the simplicity of simulated anatomic and physiological characteristics in available models. Our purpose was to develop a new detailed biomathematical model in which the morphological, biophysical, and hemodynamic characteristics of an intracranial AVM are replicated more faithfully. The technique of electrical network analysis was used to construct the biomathematical AVM model to provide an accurate rendering of transnidal and intranidal hemodynamics. The model represented a complex, noncompartmentalized AVM with 4 arterial feeders (with simulated pial and transdural supply), 2 draining veins, and a nidus consisting of 28 interconnecting plexiform and fistulous components. Simulated vessel radii were defined as observed in human AVMs. Common values were assigned for normal systemic arterial pressure, arterial feeder pressures, draining vein pressures, and central venous pressure. Using an electrical analogy of Ohm's law, flow was determined based on Poiseuille's law given the aforementioned pressures and resistances of each nidus vessel. Circuit analysis of the AVM vasculature based on the conservation of flow and voltage revealed the flow rate through each vessel in the AVM network. Once the flow rate was established, the velocity, the intravascular pressure gradient, and the wall shear stress were determined. Total volumetric flow through the AVM was 814 ml/min. Hemodynamic analysis of the AVM showed increased flow rate, flow velocity, and wall shear stress through the fistulous component. The intranidal flow rate varied from 5.5 to 57.0 ml/min with and average of 31.3 ml/min for the plexiform vessels and from 595.1 to 640.1 ml/min with an average of 617.6 ml/min for the fistulous component. The blood flow velocity through the AVM nidus ranged from 11.7 to 121.1 cm/s with an average of 66.4 cm/s for the plexiform vessels and from 446.9 to 480 dyne/cm2 with an average of 463.5 dyne/cm2 for the fistulous component. The wall shear stress ranged in magnitude from 33.2 to 342.1 dyne/cm2 with an average of 187.7 dyne/cm2 for the plexiform vessels and from 315.9 to 339.7 cm/s with an average of 327.8 cm/s for the fistulous component. The described novel biomathematical model characterizes the transnidal and intranidal hemodynamics of an intracranial AVM more accurately than was possible previously. This model should serve as a useful research tool for further theoretical investigations of intracranial AVMs and their hemodynamic sequelae.

Abstract

The results of surgery on multiple intracranial aneurysms tha involve the vertebrobasilar circulation are poor, and associated patient mortality remains high. We describe the endovascular treatment of four patients with mutiple aneurysms that involved the posterior intracrancial circulation. Satisfactory occlusion of all aneurysms was achieved by using electrolytically detachable coils, and all patients had a good clinical recovery. Our early experience suggests that endovascular coil occlusion may be a particularly suitable method for treating this high-risk condition.

Abstract

We assessed the suitability of a swine experimental arteriovenous malformation model for laboratory simulations and training in endovascular embolotherapy. Embolizations with liquid glue or particles were performed in 10 animals. The parameters of injection (microcatheter position, concentration and volume of embolic agent, injection rate) were deliberately varied to simulate results that may be observed in clinical practice. A range of successful and less desirable therapeutic outcomes or complications was simulated. In one model, intravascular mean blood pressure in the "terminal feeder" rose after "nidus" embolization, consistent with observations in feeders of cerebral arteriovenous malformations. Experience in the technical aspects of embolotherapy was gained by repeated performances using this model. Simplicity of creation, clear angiographic visibility of feeders, a nidus and a draining vein, and hemodynamic similarities with cerebral arteriovenous malformations make this an attractive in vivo experimental model for learning the principles of embolotherapy, testing new embolic agents, and training/gaining experience in embolization techniques.

Abstract

Results in nine patients with large or giant fusiform intracranial aneurysms that were treated with Guglielmi detachable coils (GDCs) are reported. There were six males and three females between the ages of 12 and 63. Four patients presented with subarachnoid hemorrhage (SAH) and four with mass effect; in one patient the aneurysm was asymptomatic and located in an arterial feeder of an arteriovenous malformation. Five aneurysms were supratentorial and four were in the posterior fossa. Five were giant and four were large. Selective occlusion with preservation of the parent artery was attempted in three cases, and complete occlusion of the aneurysm and the parent artery was performed in six patients. The tolerance to parent artery occlusion was assessed by angiography, balloon test occlusion, and amytal testing. Six aneurysms were permanently occluded and two partially recanalized. In one case, GDC embolization was not possible. The four patients who presented with SAH made an excellent clinical recovery. Three of the four patients presenting with mass effect recovered completely and one remained unchanged. The patient with an incidental aneurysm remained asymptomatic. There were no permanent complications. In conclusion, GDCs were useful for the occlusion of large and giant intradural fusiform aneurysms. Occlusion of the aneurysm and the parent artery afforded the greatest opportunity for a complete cure. Advantages of GDCs compared to balloons include: occlusion of a shorter segment of normal artery, no traction on the parent vessel, and safer and easier catheterization techniques.

Abstract

To assess the biomechanical feasibility of treating experimental fusiform aneurysms endovascularly with a combination of stents and coils.An experimental model was surgically constructed in the necks of nine swine to simulate intracranial fusiform aneurysms possessing important "perforators" or side branches. Balloon-expandable metal stents were positioned across the aneurysms in eight swine. In five of these, additional treatment was intraaneurysmal placement of detachable microcoils. Attempts were made to deposit these coils strategically away from the origin of the side branch.Stent placement was successful in seven swine but failed in one swine because of stent-aneurysm size mismatch. Two swine treated with only stents showed no significant alterations in blood filling of the aneurysm or side branch. Satisfactory coil placement (outside the stent, within the aneurysm sac, and away from the orifice of the side branch) was achieved in four of the five swine treated with stents and coils. Careful fluoroscopic monitoring and controlled coil delivery were necessary to avoid covering the sidebranch origin. These aneurysms could not be packed densely after detachment of the first coil because of the resultant radiographic overlap of multiple coil loops on the stent and its lumen in all projections. In one swine there was inadvertent untoward reentry of the coil tip into the expanded stent lumen during its delivery.Endovascular treatment of experimental fusiforms aneurysms using stents and coils is technically feasible. The stent maintains patency of the parent artery while allowing strategic coil placement in the aneurysm sac away from the origin of side branches. This technique may prove useful in the future treatment of intracranial fusiform aneurysms. However, potential sources of technical difficulties have been identified, and further longterm studies using an appropriate intracranial stent will be necessary before human application.

Abstract

Superselective angiography is the most accurate technique in the analysis of brain arteriovenous malformation (AVM) angioarchitecture. Therefore, we reviewed the selective and superselective angiograms of 100 consecutive patients with intracerebral AVMs. Our purpose was to determine which parameters of angioarchitecture were significantly correlated with a clinical presentation of hemorrhage. The vascular characteristics evaluated on the angiograms were the size of the AVM, the location of the AVM, the type of nidus, the type of feeders, the characteristics of venous drainage, and the number and location of aneurysms. The parameters found to correlate with hemorrhage were deep venous drainage (P = 0.01), feeding by perforators (P = 0.01), intranidal aneurysm(s) (P = 0.004), multiple aneurysms (P = 0.001), feeding by the vertebrobasilar system (P = 0.002), and location in the basal ganglia (P = 0.04). Six parameters of AVM angioarchitecture were correlated with a clinical presentation of hemorrhage. Among these parameters, three (feeding by perforators, number of aneurysms, and presence of intranidal aneurysms) were well displayed by superselective angiogram.

Abstract

Accurate measurement of the aneurysm neck size from diagnostic angiograms is crucial in the consideration and implementation of interventional embolotherapeutic procedures. Due to inherent problems in angiography, aneurysm morphology and location, and obstruction by overlying structures, accurate measurement of the aneurysm neck size is difficult. We are proposing a method for the angiographic measurement of aneurysm neck size based on a biomathematical model of an aneurysm. A biomathematical model of an intracranial saccular aneurysm was developed based on Laplace's law for a spherical elastic object, given by: Stress = Pressure x Radius/2 x Wall thickness. In addition, another biomechanical parameter used to describe an elastic sphere is the strain: Strain = delta R/Ri = (R-Ri)/Ri where R is the current aneurysm radius and Ri is the initial radius prior to aneurysm development. The stress and strain of an elastic structure are used to describe the elastic modulus, E: E = stress/strain = [PR/2h]/[(R-Ri)/Ri] = [PRRi]/[2hR-2hri]. It is assumed at this point that no additional tissue growth occurs through the developmental course of the aneurysm. The expression for E is now solved for Ri which, in essence, represents the radius of the aneurysm neck: Ri = [2hER]/[PR + 2hE]. Thus, the diameter of the neck, Dn, is given by Dn = 2 + i = 2 ([2hER]/[PR + 2hE]). During diagnostic angiography, the radius, R, and pressure, P, are easily obtained during the examination procedure. However, it is not possible to angiographically determine the elastic modulus, E, and the wall thickness, h. In this case, the following average values are used: E = 1.0 MPa and h = 50 microns. From the diagnostic angiograms and hospital records of 23 patients, the aneurysm neck size was determined using the biomathematical model and compared to the results obtained from the correlative relationship between the measured and accepted ratios of neck size to diameter of parent artery. The neck diameter as measured from the accepted ratios of neck size to parent artery diameter for the 23 patients ranged from 1.5 mm to 8.7 mm. The angiographically measured neck sizes were in excellent agreement with those obtained from the biomathematical model, particularly for the wide-necked aneurysms, as evidenced by the fact that all but two chi 2 values were < 1.0. We have described a simple yet accurate method for obtaining aneurysm neck size measurements from diagnostic angiograms using a biomathematical model. The model requires knowledge of only the aneurysm radius and blood pressure and becomes particularly important in characterizing wide-necked aneurysms.

Abstract

To evaluate the histologic and angiographic effects of collagen microbeads as an embolic agent in the swine rete mirabile.Human collagen particles (380 +/- 100 microns) of spheroidal shape and smooth surface were used to embolize the rete mirabile in five swine. Control angiograms and pathologic examinations were obtained immediately and sequentially from 3 to 35 days after embolization.The collagen particles were easy to inject through microcatheters. Embolization was always angiographically complete and persistent for at least 5 weeks. Histologic studies showed occlusion of 25% to 50% of the rete vessels. After 3 and 5 weeks' follow-up, transmural and adventitial chronic inflammation was present. Inflammatory infiltrates included lymphohistiocytic cells and scattered eosinophils. The foreign-body giant-cell reaction was pronounced. No evidence of angionecrosis or focal hemorrhage was shown.Collagen microbeads are a promising experimental embolic agent, with potential future applications in humans.

Abstract

We present a case of a young adult in whom acute subdural hemorrhage developed immediately after embolization of a cerebral arteriovenous malformation with glue. Inadvertent venous outlet obstruction with glue was implicated in the production of the hemorrhage. Possible mechanisms of spread of blood to the subdural space are discussed. Awareness of the possibility of iatrogenic subdural hemorrhage is necessary before undertaking embolization procedures.

Abstract

To identify the morphological vascular characteristics of cerebral arteriovenous malformations (AVMs) that predict a clinical presentation of epilepsy.Fifteen angioarchitectural characteristics of brain AVMs were selected for assessment in 100 consecutive patients referred to our institution for endovascular treatment. In this population, 47% of the AVMs were diagnosed as a consequence of epilepsy. The angioarchitectural characteristics and population demographics were statistically analyzed by means of multivariate analysis.The following six parameters were found to be the most predictive of epilepsy: cortical location of the AVM, feeding by the middle cerebral artery, cortical location of the feeder, absence of aneurysms, presence of varix/varices in the venous drainage, and association of varix and absence of intranidal aneurysms. Three factors were not among the most predictive factors of epilepsy but were significantly associated with the onset of seizures: AVM feeding by the external carotid artery, a temporal cortical location, and a parietal cortical location.Detailed analysis of the angioarchitecture of intracranial AVMs has helped us identify features that strongly correlate with epilepsy. This may aid in future understanding of the physiopathologic mechanisms in epilepsy associated with AVMs, and in identifying goals of treatment for epileptogenic AVMs.

Abstract

Laplace's law, which describes a linear relation between the tension and the radius, is often used to characterize the mechanical response of the aneurysm wall to distending pressures. However, histopathological studies have confirmed that the wall of the fully developed aneurysm consists primarily of collagen and is subject to large increases in tension for small increases in the radius, i.e., a nonlinear relationship exists between the tension within the aneurysm wall and the radius. Thus, a nonlinear version of Laplace's law is proposed to accurately describe the development and rupture of a fusiform saccular aneurysm. The fusiform aneurysm was modelled as a thin-walled ellipsoidal shell with a major axis radius, Ra, minor axis radius, Rb, circumferential tension, S0, and meridional tension, S phi, with phi defining the angle from the surface normal. Using both linear and nonlinear models, differential expressions of the volume distensibility evaluated at 90 degrees were used to determine the critical radius of the aneurysm along the minor axis from S0 and S phi in terms of the following geometric and biophysical variables; A, elastic modulus of collagen; E, elastic modulus of the aneurysm (elastin and collagen); t, wall thickness; P, systolic pressure; and Ra. For typical physiological values of A = 2.8 MPa, E = 1.0 MPa, T = 40 microns, P = 150 mmHg, and Ra = 4Rb, the linear model yielded critical radii of 4.0 mm from S phi and 2.2 mm from S0. The resultant critical radius was 4.56 mm. Using the same values, the critical radii from the tension components of the nonlinear model were 3.5 mm from S phi and 1.9 mm from S0.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Mathematical models of aneurysms are typically based on Laplace's law which defines a linear relation between the circumferential tension and the radius. However, since the aneurysm wall is viscoelastic, a nonlinear model was developed to characterize the development and rupture of intracranial spherical aneurysms within an arterial bifurcation and describes the aneurysm in terms of biophysical and geometric variables at static equilibrium. A comparison is made between mathematical models of a spherical aneurysm based on linear and nonlinear forms of Laplace's law. The first form is the standard Laplace's law which states that a linear relation exists between the circumferential tension, T, and the radius, R, of the aneurysm given by T = PR/2t where P is the systolic pressure. The second is a 'modified' Laplace's law which describes a nonlinear power relation between the tension and the radius defined by T = ARP/2At where A is the elastic modulus for collagen and t is the wall thickness. Differential expressions of these two relations were used to describe the critical radius or the radius prior to aneurysm rupture. Using the standard Laplace's law, the critical radius was derived to be Rc = 2Et/P where E is the elastic modulus of the aneurysm. The critical radius from the modified Laplace's law was R = [2Et/P]2At/P. Substituting typical values of E = 1.0 MPa, t = 40 microns, P = 150 mmHg, and A = 2.8 MPa, the critical radius is 4.0 mm using the standard Laplace's law and 4.8 mm for the modified Laplace's law.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Experimental models of intracranial saccular aneurysms are a useful contribution to our basic understanding of these lesions. Currently, the commonest in use are those constructed surgically in laboratory animals. We review the numerous surgical techniques available since the 1950s, and the research applications and uses of experimental aneurysms. Further development and use of such models is greatly encouraged in future pathophysiological, hemodynamic, and therapeutic investigations of intracranial saccular aneurysms.

Abstract

A new technique for surgical construction of experimental lateral saccular aneurysms on the common carotid artery of swine is described. It involves end-to-side suturing of an isolated segment of vein to an artery. During a short period of parent artery clamping, an elliptical arteriotomy is fashioned through the open-ended vein graft, the open end of which is subsequently tied and clamps are removed to form an aneurysmal vein pouch. The principal advantage of this technique is the short period of vascular clamping necessary to isolate a segment of the parent artery. This prevents severe endothelial injury and prolonged postoperative vasospasm, both of which may promote intra-aneurysmal thrombosis. Narrow- or wide-necked aneurysms can be created. Steps in the surgical construction of this model are detailed, and specific advantages of using swine are highlighted.

Abstract

To report the comprehensive superselective angiographic characteristics of aneurysms associated with cerebral arteriovenous malformations.One hundred consecutive patients referred for cerebral arteriovenous malformation embolization underwent preembolization superselective angiography. Superselective angiograms were obtained after microcatheterization of arteriovenous malformation pedicles, and assessed for number and location of aneurysms related to the malformation. A chi 2 test was conducted to correlate these parameters with the onset of intracranial hemorrhage.Aneurysms were demonstrated in 58 of 100 patients. Single aneurysms were found in 24 patients and multiple aneurysms in 34. Presence and number of aneurysms were found to correlate significantly with a clinical presentation of hemorrhage.Superselective angiography was found to be of paramount importance in elucidating the precise and detailed angioarchitecture of brain arteriovenous malformations.

Abstract

Moyamoya disease (MMD) often presents with subarachnoid hemorrhage due to rupture of saccular aneurysms. We describe three patients with cerebrovascular features of MMD in whom four aneurysms of the posterior circulation were endovascularly occluded by electrothrombosis using the recently developed Guglielmi electrically detachable coils (GDC). Near total occlusion was achieved in three aneurysms. Subtotal occlusion was achieved in one aneurysm. This patient developed complications related to the neuroleptic anesthesia administered for the procedure. The particular hazards of anesthesia and aneurysmal surgery in MMD are discussed, and comparison is made with the benefits of using the GDC. Initial experience suggests that this endovascular approach is safe and effective in the treatment of saccular aneurysms in MMD. However, follow-up is necessary to assess long-term persistence of aneurysm obliteration.

Abstract

To assess the feasibility of combining stent implantation in the parent artery with endosaccular coil placement for the treatment of experimentally created wide-necked aneurysms.Wide-necked aneurysms were surgically created on the common carotid artery in 12 swine. A metal stent was endovascularly implanted across each aneurysm neck and its effect documented anigiographically. If the aneurysm remained patent, a microcatheter was introduced into the aneurysm through the stent mesh. Electrically detachable coils were delivered into the aneurysm sac to produce thrombosis.After stent implantation, one carotid artery thrombosed and two aneurysms spontaneously occluded. In the other 9 cases, coils were deposited through the stent to occlude the aneurysm. Complete aneurysm packing was possible in all 9 cases. The presence of the stent allowed placement of small coils near the aneurysm neck, thus contributing to the safe occlusion of small remnants in the final stages of aneurysm packing.The combination of stent implantation and coil placement is feasible in the treatment of experimental wide-necked saccular aneurysms. The stent maintains patency of the parent artery while allowing aneurysm occlusion by endosaccular coil placement through the stent's mesh. Occlusion of small aneurysm remnants is possible with no fear of coil hernation or migration into the parent artery. Long-term studies will be necessary before application to treatment of selected intracranial aneurysms.

Abstract

We report our preliminary experience in the surgical construction of five experimental bifurcation and terminal aneurysm models in swine. We used unilateral neck vessels to construct models in which the relative directions and sizes of the parent and daughter arteries could be varied by surgery, resulting in aneurysms with high morphologic similarity to human intracranial lesions. Steps in the construction of each model are detailed.

Abstract

Sodium picosulphate (Picolax) is widely used for bowel preparation prior to colonic investigation or surgery. The most troublesome side effect reported is headache, which has been thought to be due to dehydration. In a prospective randomized study we investigated the incidence of adverse effects in patients given Picolax prior to barium enema examination, and assessed the incidence of adverse effects with different oral fluid regimens. A total of 197 outpatients were allocated to one of five fluid regimens on the day prior to the enema: (a) 4 pints of Dioralyte (glucose and electrolyte solution); (b) 4 pints of half-strength Dioralyte; (c) 4 pints of water; (d) 6 pints of water; and (e) free fluids. In a questionnaire, 36% of patients had no headache (graded 0/5), while 38% had a significant headache (graded 3/5 or greater). Sixteen per cent had significant abdominal pain, 42% had dry mouths, 43% thirst and 34% tiredness or irritability. There was no correlation between headache and fluid regimen. Furthermore, we have found no evidence of dehydration. None of the five fluid regimens was shown to offer any advantage, and we therefore recommend that patients be allowed to drink according to thirst when taking Picolax.

Abstract

Nasolacrimal duct obstruction and consequent epiphora is a complication that may develop in some patients following paranasal sinus surgery. We describe the technique of CT-dacryocystography which entails contrast injection of the lacrimal system and simultaneous computed tomography (CT) scanning of the facial structures. This technique provides concurrent information regarding obstruction of the nasolacrimal duct and the presence of disease recurrence or persistence in the adjacent paranasal sinuses. The role of CT-dacryocystography prior to endoscopic dacryocystorhinostomy is discussed briefly.

Abstract

A search of the literature suggests that the conventional 20 mg dose of intravenous hyoscine-N-butylbromide (HBB) for smooth muscle relaxation in double-contrast barium meal (DCBM) studies is largely empirical. This study analysed the merits of three different doses (5 mg, 10 mg, 20 mg) in the performance of routine DCBMs. One hundred and twenty DCBM examinations were prospectively and randomly allocated to receive one of three doses. Three parameters were measured for each examination: gastroduodenal distension, delay in gastric emptying and gastric antrum overlapping with barium-filled duodenal loops. Almost half the examinations using 5 mg produced undesirable duodenal-gastric overlay. Unacceptable early flooding of the duodenal bulb with barium was seen mostly with doses of 5 mg and 10 mg. Overall, the best results were obtained with 20 mg. The continued use of 20 mg HBB in routine DCBMs is recommended.

Abstract

Thyroglossal fistulography is poorly documented in the radiological literature. An illustrative case is presented, highlighting the technique employed and the significance of its findings. The taste of contrast medium as it spills over the tongue is a useful additional sign in the successful demonstration of a fistulous communication. The contribution of fistulography to the accurate diagnostic work-up of patients undergoing the Sistrunk procedure is discussed.

Abstract

Subarachnoid hemorrhage due to spontaneous dissection of intracranial vessels is uncommon. Most such cases are confined to the posterior circulation. Dissection of an intracranial carotid artery producing subarachnoid hemorrhage without a focal ischemic event is rarely documented. We report a case and review the subject.

Abstract

Colonic carcinomas may be missed on the barium enema examination for a variety of perceptive, technical, and interpretive reasons. We report an uncommon source of error-persistent bowel spasm resulting in concealment of an underlying carcinoma. Awareness of this association is necessary in the effort to minimize diagnostic pitfalls of the barium enema examination.

Abstract

The radiographs of 60 patients having double-contrast barium meal examinations were analysed by a linear analogue technique to assess variation in the quality of mucosal coating between morning and afternoon studies. No significant difference (P greater than 0.5) was found between morning and afternoon gastric mucosal coating. Factors that could in theory contribute to a diurnal variation are discussed. We conclude that afternoon DCBMs can be confidently booked and performed, in the knowledge that their diagnostic quality is not impaired.

Comment on the article by Barloon et al, in which hemodilution was found to occur after enteroclysis in patients with partial small bowel obstruction.Investigative radiologyMassoud, T. F., Nolan, D. J.1990; 25 (9): 1066-?